摘要Ferroptosis plays a key role in nerve injury in intracerebral hemorrhage and is associated with the upregulation of murine double minute 2.Investigating the mechanism underlying murine double minute 2-related ferroptosis could help identify new therapies for intracerebral hemorrhage.An in vitro intracerebral hemorrhage model was established by treating BV2 microglial cells with oxygen-glucose deprivation combined with hemin.The role of murine double minute 2 in regulating ferroptosis was investigated via transduction with RNA interference and lentivirus overexpression.Furthermore,intracerebral hemorrhage mouse models were constructed with and without an murine double minute 2 inhibitor(brigimadlin),and behavioral assays were performed to assess the learning ability and cognitive function.Murine double minute 2 dysregulation was associated with oxygen-glucose deprivation combined with hemin-induced BV2 microglial cell ferroptosis and M1/M2 polarization.The results suggested that murine double minute 2 induced glutathione peroxidase 4 ubiquitination and degradation to regulate ferroptosis and inflammatory responses in BV2 microglial cells.Mechanistically,Wilms tumor 1-associated protein induced murine double minute 2 N6-methyladenosine(m6A)modification and regulated ferroptosis and inflammatory responses.In vivo analysis showed that brigimadlin improved neurological deficits and spatial memory in mice with intracerebral hemorrhage.In summary,the results indicate that Wilms tumor 1-associated protein regulates murine double minute 2 m6A modification,and murine double minute 2 induces glutathione peroxidase 4 ubiquitination and degradation.This regulation promotes ferroptosis and inflammatory responses in oxygen-glucose deprivation combined with hemin-induced BV2 microglial cells,suggesting that the murine double minute 2-glutathione peroxidase 4-ferroptosis regulatory axis exerts neurotoxic effects.These findings identify glutathione peroxidase 4 as a potential gene therapy target for intracerebral hemorrhage-related brain injury.